Fatal episodes of asthma are associated with profound mucus hypersecretion and mucus plugging of the airways. Despite the association of mucus hypersecretion with the morbidity and mortality of asthma, the mechanisms governing the abnormal production of mucus remain elusive. Recently, we and others have shown that the Th2 cytokine, IL-13, is an important regulator of mucus cell metaplasia and asthma pathogenesis. However, the exact mechanisms by which IL-13 regulates mucus production are not known. The overall goal of this proposal is to define the molecular mechanisms underlying IL-13- induced goblet cell metaplasia (GCM). Our preliminary data suggest that IL-13 induces goblet cell metaplasia and mucus secretion via direct actions on the airway epithelium. Furthermore, a preliminary query of IL-13-induced gene expression patterns suggests that IL-13-induced GCM is associated with the upregulation of epidermal growth factor receptor signaling pathways and the expression of a newly described Ca activated chloride channel. Thus, we hypothesize that IL-13 induces GCM through the coordinate regulation of EGFR signaling pathways and Ca activated chloride channel activity. To test this hypothesis, we propose the following specific aims: 1) to define the exact sequence of events induced by IL-13 in primary murine and human epithelial cells; 2) to determine the role of EGFR signaling pathways in IL-13-induced mucus cell changes; 3) to determine the role that the newly described family of Ca activated chloride channels plays in regulating mucus cell differentiation and mucus release; and 4) to determine the relationship between IL-13-mediated pathways and mucus hypersecretion in human asthma. A better understanding of the mechanisms underlying IL-13-induced mucus hypersecretion should guide the development of novel strategies for the treatment of asthma and other hypersecretory diseases of the lung.